Dichloromethane → Tert-butyl((1r)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2h-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)carbamate

Temperature

90 °C

A mixture of potassium acetate (2.92 g, 29.8 mmol), the above carbamate (3.17 g, 9.9 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.77 g, 10.9 mmol) was dissolved in 10 mL of DMSO in a sealed tube reaction vessel caped with a rubber septum. This heterogeneous mixture was then evacuated and purged with nitrogen three times prior to introduction of [1,1′-bis-(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with DCM (1:1) (0.363 g, 0.500 mmol). The heterogeneous mixture was then evacuated and purged with nitrogen twice before the septum was replaced with a teflon screw-top cap. This sealed vessel was then heated to 90° C. for 16 hours. After cooling to ambient temperature, potassium carbonate (2.74 g, 19.9 mmol), water (9.9 mL), 5-(2-bromo-4-chloro-6-fluorophenyl)-2-methyl-2H-tetrazole (3.04 g, 10.4 mmol) and additional palladium catalyst (0.363 g, 0.500 mmol) were added and the reaction vessel was sealed again. After heating to 80° C. for 5 hours, the reaction was cooled and then quenched with water. The mixture was flushed through a plug of celite and chased with EtOAc. The aqueous layer was extracted once with EtOAc. The combined organic layers were washed with water and brine prior and dried over sodium sulfate. Filtration and solvent removal provided material which was subjected to silica gel chromatography eluting with 0-10% EtOAc in hexanes to yield tert-butyl((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)carbamate. This material was dissolved in 15 mL of dry EtOAc. Anhydrous HCl gas was then bubbled through the solution for 3 minutes. The reaction was stirred vigorously for one hour. The reaction mixture was slowly neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was partitioned between water and EtOAc. The organic layer was washed with water and brine and dried over sodium sulfate. Filtration and concentration provided the title compound as an oil.

1. customcaped with a rubber septum
2. customThis heterogeneous mixture was then evacuated
3. custompurged with nitrogen three times
4. customThe heterogeneous mixture was then evacuated
5. custompurged with nitrogen twice before the septum
6. temperatureAfter cooling to ambient temperature
7. customthe reaction vessel was sealed again
8. temperatureAfter heating to 80° C. for 5 hours
9. temperaturethe reaction was cooled
10. customquenched with water
11. customThe mixture was flushed through a plug of celite and chased with EtOAc
12. extractionThe aqueous layer was extracted once with EtOAc
13. washThe combined organic layers were washed with water and brine
14. dry with materialdried over sodium sulfate
15. filtrationFiltration and solvent removal
16. customprovided material which
17. washeluting with 0-10% EtOAc in hexanes

ORD record

ord-95dd77b8230e4f559b54da5030e783de

Source dataset

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07816380B2